It is well described that insulin deficient, ketosis prone, diabetic patients do not respond normally to insulin, and, in general, this insulin resistance is worse the more insulin deficient the patient. Experimental Streptozotocin diabetes leads to a state of severe insulin deficiency in rats. This is associated with in vivo and in vitro decreases in tissue glucose metabolism and insulin responsiveness, and these findings are likely to be analogous to in vivo observations in insulin dependent, diabetic patients. However, insulin's physiologic effects on glucose metabolism are complex and depend upon the interaction between insulin--receptors--and effector systems. Therefore, each of these steps must be separately studied in order to fully understand the cellular abnormalities which result in decreased insulin sensitivity in this situation. Additionally, it is our hypothesis that insulin has a direct (trophic?) effect in maintaining the integrity of the glucose transport system. Therefore, we propose to study the effects of various degrees of experimental insulin deficiency on insulin binding, glucose transport, and glucose oxidation using isolated adipocytes from Streptozotocin diabetic rats. Furthermore, we propose the converse studies in which these cellular processes will be examined in animals made experimentally hyperinsulinemic by a 14-day regimen of twice daily injections of NPH insulin. This hyperinsulinemic animal will also serve as a model to assess the role of hyperinsulinemia per se in the development of the insulin resistance of various hyperinsulinemic-insulin resistant states. Finally, we will also evaluate the reversibility of these cellular abnormalities by studying the effects of insulin replacement or withdrawal, respectively, on the abnormalities produced. Clearly, only by knowing basic mechanisms can the metabolic abnormalities of diabetes and obesity be understood and in this way a more physiologic rationale for therapy can be devised.